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The prevalence and characterization of migraine triggers have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined trigger factors in a clinic-based population. In 102 children and adolescents fulfilling the Second Edition of The International Headache Classification criteria for paediatric migraine, at least one migraine trigger was reported by the patient and/or was the parents’ interpretation in 100% of patients. The mean number of migraine triggers reported per subject was 7. Mean time elapsed between exposure to a trigger factor and attack onset was comprised between 0 and 3 h in 88 patients (86%). The most common individual trigger was stress (75.5% of patients), followed by lack of sleep (69.6%), warm climate (68.6%) and video games (64.7%). Stress was also the most frequently reported migraine trigger always associated with attacks (24.5%). In conclusion, trigger factors were frequently reported by children and adolescents with migraine and stress was the most frequent.

Recently an early onset lethal encephalopathy has been described in relation to mutations of NFU1 , one of the genes involved in iron-sulfur cluster metabolism. We report a new NFU1 mutated patient presenting with a milder phenotype characterized by a later onset, a slowly progressive spastic paraparesis with relapsing-remitting episodes, mild cognitive impairment and a long survival. The early white matter abnormalities observed on MRI was combined with a mixed sensory-motor neuropathy in the third decade. Our case clearly suggests the importance of considering NFU1 mutation in slowly evolving leukoencephalopathy with high glycine concentration.

BackgroundMicroRNAs (miRNAs) are non-coding gene transcripts involved in post-transcriptional regulation of genes. Recent studies identified miRNAs as important regulators of learning and memory in model organisms. So far, no mutations in specific miRNA genes have been associated with impaired cognitive functions.Methods and resultsIn three sibs and two unrelated patients with intellectual disability (ID), overlapping 1p21.3 deletions were detected by genome-wide array analysis. The shortest region of overlap included dihydropyrimidine dehydrogenase (DPYD) and microRNA 137 (MIR137). DPYD is involved in autosomal recessive dihydropyrimidine dehydrogenase deficiency. Hemizygous DPYD deletions were previously suggested to contribute to a phenotype with autism spectrum disorder and speech delay. Interestingly, the mature microRNA transcript microRNA-137 (miR-137) was recently shown to be involved in modulating neurogenesis in adult murine neuronal stem cells. Therefore, this study investigated the possible involvement of MIR137 in the 1p21.3-deletion phenotype. The patients displayed a significantly decreased expression of both precursor and mature miR-137 levels, as well as significantly increased expression of the validated downstream targets microphthalmia-associated transcription factor (MITF) and Enhancer of Zeste, Drosophila, Homologue 2 (EZH2), and the newly identified target Kruppel-like factor 4 (KLF4). The study also demonstrated significant enrichment of miR-137 at the synapses of cortical and hippocampal neurons, suggesting a role of miR-137 in regulating local synaptic protein synthesis machinery.ConclusionsThis study showed that dosage effects of MIR137 are associated with 1p21.3 microdeletions and may therefore contribute to the ID phenotype in patients with deletions harbouring this miRNA. A local effect at the synapse might be responsible.

Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.

We aimed to assess brain regional glucose uptake (rGlcU) changes in children with isolated cerebellar cortical dysplasia (CCD) using 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET). Six children aged 9 months to 11 years at the time of diagnosis, carrying isolated CCD (with no other associated posterior fossa or supratentorial malformation) underwent a brain FDG-PET and a subsequent 3DT1-weighted MRI for coregistration. The MRIs acquired previously at the time of diagnosis were reviewed to record the cerebellar dysplastic features and classify the patients as having minor, moderate, or severe CCD. The individual rGlcU was assessed qualitatively on coregistrated FDG maps. Clinical data from birth, including neurological and neuropsychological (verbal and motor skills) disturbances, were recorded. We found rGlcU changes within the cerebellum of four patients matching with the location and extent of structural abnormalities: hypometabolism in three patients with severe CCD involving the vermis and both cerebellar hemispheres and focal hypermetabolism in one patient with moderate CCD associated with a nodular heterotopic gray matter. No obvious rGlcU changes were found in the two patients with minor CCD involving the vermis only. Supratentorial rGlcU changes found commonly involved the basal ganglia bilaterally. Coregistrated FDG-PET/MRI technique is useful in detecting cerebellar cell dysfunction associated with isolated CCD. Our results enhance the need for multimodal and quantitative studies to better evaluate local and remote functional disturbances caused by CCD.

The aim of this 6-month, prospective, multicenter study of 398 children and adolescents with primary headaches was to collect data on headache treatment in neuropediatric departments. Treatments were compared before and after consultation. Prior to consultation, the acute treatments that had been prescribed most frequently were paracetamol (82.2% of children) and non-steroidal anti-inflammatory drugs treatment (53.5%); 10.3% had received a prophylactic treatment. No differences in either acute or prophylactic treatment with respect to headache diagnosis were observed. After the neuropediatric consultation, paracetamol was replaced by a non-steroidal anti-inflammatory drug in about three-quarters of cases and by triptan in about one-quarter of cases. The number of children prescribed a prophylactic treatment nearly doubled, whereas there was a 5-fold and 23-fold increase in psychotherapy and relaxation training, respectively, between pre-referral and referral. We conclude that specific treatments were underused for primary headache.

Few data are available on the applicability of both the criteria proposed by Silberstein and Lipton (S-L) and the International Classification of Headache Disorders-II (ICHD-II) in the classification of children and adolescents with chronic daily headache (CDH). The International Headache Society recently added revised criteria (ICHD-IIR) for chronic migraine to its Appendix. We retrospectively reviewed all charts of 34 children and adolescents (<17 years) with primary CDH presenting to the outpatient clinic of the Universitary Department of Neuropediatrics of Lille between February 2004 and February 2006 and tried to classify their CDH according to both S-L criteria and the recently published ICHD-IIR. Thirty-two children (94%) and 33 children (97%) could respectively be successfully classified into one subtype of CDH according to the S-L classification and the ICHD-IIR. Transformed migraine was the most common diagnosis (61.8%), followed by new daily-persistent headache (20.6%) when the S-L criteria were used. Twenty-three children and adolescents (67.6%) could be classified under one of the migraine categories according to the ICHD-IIR classification. We think that both S-L and ICHD-II classifications, when used with detailed headache histories and diaries, are adequate to classify chronic daily headache in children and adolescents.

Objective Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2‐deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT. Methods The trial was a 6‐month, multicenter, randomized, double‐blind, placebo‐controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2–3 mg/kg Desipramine per day (high Desipramine), 1–2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention‐to‐treat analysis was applied. Results The median change in AHI from baseline to 6 months was −31 (IQR: −37 to −11) for the high Desipramine, −17.5 (IQR: −31 to 13) for the low Desipramine, and −13 (IQR:−31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = −0.44; P = 0.0002) was underlined. Interpretation This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.

In mental retardation (MR) an aetiological diagnosis is not always obtained despite a detailed history, physical examination and metabolic or genetic investigations. In some of these patients, MRI is recommended and may identify subtle abnormal brain findings. We reviewed the cerebral MRI of children with non-specific mental retardation in an attempt to establish a neuroanatomical picture of this disorder. Thirty children with non-specific MR were selected to undergo cerebral MRI. The examination included supratentorial axial slices, mid-sagittal images and posterior fossa coronal images. Brain malformations, midline and cerebellar abnormalities were studied. In 27 of 30 patients, the neuroimaging evaluation revealed a relatively high incidence of cerebral and posterior fossa abnormalities. The most frequent were: dysplasia of the corpus callosum (46%; hypoplasia, short corpus callosum and vertical splenium), partially opened septum pellucidum and/or cavum vergae (33%), ventriculomegaly (33%), cerebral cortical dysplasia (23%), subarachnoid space enlargement (16.6%), vermian hypoplasia (33%), cerebellar and/or vermian disorganised folia (20%), and subarachnoid spaces enlargement in the posterior fossa (20%). Other anomalies were: enlarged Virchow-Robin spaces (10%), white matter anomalies (10%) and cerebellar or vermian atrophy. MRI has shown a high incidence of subtle cerebral abnormalities and unexpected minor forms of cerebellar cortical dysplasia. Even if most of these abnormalities are considered as subtle markers of brain dysgenesis, their role in the pathogenesis of mental retardation needs further investigation.

Genomic balance: underweight as a mirror image of obesity Underweight and obese phenotypes can both pose health risks. But whereas obesity has been associated with a number of genetic variants, little is known about the genetic basis of underweight. A large-scale screen of data from 28 cytogenetic centres in Europe and North America now shows that being underweight is frequently associated with duplication of a short region on chromosome 16. Deletion of this same chromosomal region has previously been associated with obesity. The observed associated phenotypes are opposites, or mirrors, of those reported in carriers of deletions at this locus, and correlate with changes in transcript levels for genes within the duplication but not within the adjacent regions. The suggestion is that severe obesity and being underweight could have mirror etiologies, possibly through contrasting effects on energy balance. Both obesity and being underweight have been associated with increased mortality 1 , 2 . Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m 2 in adults and ≤ −2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive 3 , 4 , 5 , feeding and eating disorder and/or anorexia nervosa 6 , 7 . In contrast to obesity, few genetic variants underlying these clinical conditions have been reported 8 , 9 . We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities 10 . Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.